Through an interrelated series of clinical biochemical investigations and pharmacological studies this project explores both the underlying biochemical pathophysiologies of depressive and manic disorders as well as problems concerning the mechanisms of action of drugs and other somatic interventions used in their treatment. There has been a progressive shift in the emphasis of this research program towards clinical studies during the past year although basic neuropharmacological studies continue to be an important aspect of our work. This research continues to focus on studies of biogenic amine metabolism since this has remained a most productive line of investigation. Findings of our recent clinical studies suggest that there may be biochemical differences between manic-depressive and chronic characterological depressions as reflected by differences on the urinary excretion of MHPG, the major metabolite of norepinephrine originating in brain. Moreover, our recent findings show that MHPG excretion is inversely related to REM sleep time (D-time), suggesting both that the changes in sleep patterns observed in patients with affective disorders, particularly manic-depressive disorders, may be related to alterations in catecholamine metabolism and that measurement of urinary MHPG excretion can provide meaningful information about the activity of the central nervous system. While a number of problems are currently under investigation within this project, our major emphasis is on studies of biochemical criteria for differentiating different subtypes of depressive disorders. The findings of these studies may have important practical clinical application including the development of biochemical criteria for predicting differential responses to one or another antidepressant drug.